R-spondin1 is essential in sex determination, skin differentiation and malignancy

Parma, P.; Radi, Orietta; Vidal, Valérie; Chaboissier, Marie-Christine; Dellambra, Elena; Valentini, Stella; Guerra, Liliana; Schedl, Andreas; Camerino, Giovanna

doi:10.1038/ng1907

Cited by 587 publications

(570 citation statements)

References 22 publications

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“…One of the main activators of this pathway is RSPO1 which, when mutated, gives rise to 46, XX male individuals with differentiated testes demonstrating that RSPO1 is a female sex determining gene (Parma et al, 2006). Furthermore, the lack of Rspo1 in XX mice mutant embryo leads to the loss of nuclear β-catenin indicating that the transcriptional function of β-catenin was impaired in these animals (Chassot et al, 2008).…”

Section: Is Wnt/β-catenin the Proposed "Z" Factor?mentioning

confidence: 99%

“…However, the recent discovery of mutations in the RSPO1 (R-spondin homolog 1) gene in female-to-male XX patients has challenged this view (Parma et al, 2006). Analysis of the testis structure in these patients revealed fully differentiated Sertoli and Leydig cells indicating that, in the absence of SRY, the male sex determination pathway was activated.…”

Section: Introductionmentioning

confidence: 99%

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Human SRY inhibits β-catenin-mediated transcription

Bernard

Sim

Knower

et al. 2008

The International Journal of Biochemistry & Cell Biology

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In most mammals, sex is determined by the presence or absence of the SRY gene. SRY encodes a DNA binding HMG-box transcription factor which, during embryogenesis, is the initial trigger of testis differentiation from the bipotential gonad, yet its precise mode of function remains unclear. In ovarian development, R-spondin1 and Wnt4 act through the Wnt/β-catenin signaling pathway to regulate TCF-dependent expression of unknown target genes and repress testis development. Conversely, SRY may be necessary to prevent the development of ovaries by inhibiting the action of ovarian-determining genes. We hypothesize that SRY prevents Wnt/β-catenin signaling, thereby inhibiting ovarian development. In HEK293T cells, SRY repressed β-catenin-mediated TCFdependent gene activation in the presence of a specific GSK3β inhibitor or an activated β-catenin mutant, suggesting that SRY inhibits Wnt signaling at the level of β-catenin. Three SRY mutant proteins with nuclear localization defects, encoded by XY male-to-female patients, failed to inhibit β-catenin; surprisingly four SRY sex reversed mutants with defective DNA binding activity showed near wild-type SRY inhibitory activity. Moreover the potent transactivator SRY-VP16 fusion protein also showed wild-type SRY inhibitory activity. Thus SRY inhibition of β-catenin involves neither DNA binding nor transactivation functions of SRY. β-catenin and SRY interact in-vitro and SRY expression triggered β-catenin localization into specific nuclear bodies in NT2/D1 and Hela cells. We conclude that SRY inhibits β-catenin-mediated Wnt signaling by a novel nuclear function of SRY that could be important in sex determination.

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Section: Is Wnt/β-catenin the Proposed "Z" Factor?mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human SRY inhibits β-catenin-mediated transcription

Bernard

Sim

Knower

et al. 2008

The International Journal of Biochemistry & Cell Biology

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“…Ce type d'inversion sexuelle est rencontré chez l'homme, mais aussi chez plusieurs espèces animales : le chien, le cheval, le porc et la chèvre. À l'heure actuelle, deux gènes responsables de ce type de pathologie ont pu être isolés, FOXL2 chez la chèvre et R-Spondin1 (RSPO1) chez l'homme [9,10]. Chez la chèvre, la perte de fonction du gène FOXL2 est syndromique.…”

Section: Foxl2 Un Gène Z Candidatunclassified

“…La fixation de PRDM9 sur ses cibles permet, selon un méca-nisme qui reste à découvrir, de spécifier des sites préférentiels d'initiation de la recombinaison à l'origine des points chauds. Des approches différentes ont permis à deux autres équipes d'identifier indépendamment le rôle de PRDM9 dans la spécification des points chauds de recombinaison chez la souris et chez l'homme [9,10]. Une particularité remarquable de ce mécanisme est que des changements dans les doigts de zinc de PRDM9, s'ils modifient la séquence d'ADN reconnue, suffisent à changer les cibles génomiques de PRDM9 et par conséquent à renouveler les points chauds de recombinaison dans l'ensemble du génome.…”

unclassified

“…Une particularité remarquable de ce mécanisme est que des changements dans les doigts de zinc de PRDM9, s'ils modifient la séquence d'ADN reconnue, suffisent à changer les cibles génomiques de PRDM9 et par conséquent à renouveler les points chauds de recombinaison dans l'ensemble du génome. Par exemple, les protéines PRDM9 de l'homme et du chimpanzé diffèrent fortement au niveau de leurs doigts de zinc, ce qui permet d'expliquer que, malgré des génomes aux séquences très similaires (moins de 1,2 % de divergence), les points chauds de crossing-over ne soient pas conservés entre ces deux espèces [9]. L'étude de PRDM9 a permis de mettre en évidence une évolution extrêmement rapide de ses doigts de zinc qui concerne essentiellement les acides aminés impliqués dans la spécificité des séquences d'ADN reconnues [11].…”

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FOXL2, le gardien de l’identité ovarienne

Pannetier

Pailhoux

2010

Med Sci (Paris)

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Development of the Mammalian Gonad: Key Sex‐Determining Genes in Mice and Humans

Warr

Greenfield

2016

Encyclopedia of Life Sciences

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Sex determination is the process by which an embryo commits to the male or female gonadal fate. Our understanding of mammalian sex determination is dominated by the consideration of data from humans and mouse models. Humans and mice share important elements of their reproductive biology, and therefore experimentation in the mouse offers the prospect of detailed mechanistic insights into typical and atypical human sexual development. Recent studies reveal a high degree of conservation in the roles played by sex‐determining genes in mice and humans, but also important differences. Key themes that have emerged from mouse genetics studies include the mutually antagonistic roles of testis‐ and ovary‐determining genes and the requirement to maintain these long after the primary sex‐determining event. The advent of technologies such as next‐generation sequencing and genome editing promises to shed more light on the causes of disorders of sex development in humans, as well as fundamental mechanisms in cell fate commitment in the mammalian gonad. Key Concepts The mammalian gonad (testis or ovary) develops from a bipotential primordium in which genes associated with later sexual differentiation are expressed. The testis‐ and ovary‐determining gene networks are mutually antagonistic during primary sex determination. The maintenance of cell identity in the differentiated adult gonad requires continued inhibition of opposing genetic pathways. Interpreting the nature of mutations associated with human genetic disease, including disorders of sex development (DSD), is aided by the generation and study of mouse models.

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R-spondin1 is essential in sex determination, skin differentiation and malignancy

Cited by 587 publications

References 22 publications

Human SRY inhibits β-catenin-mediated transcription

Human SRY inhibits β-catenin-mediated transcription

FOXL2, le gardien de l’identité ovarienne

Development of the Mammalian Gonad: Key Sex‐Determining Genes in Mice and Humans

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